Substituted tertiary amino compounds having valuable pharmacological properties



May 31, 1966 KRALT ETAL 3254,112

SUBSTITUTED TERTIARY AMINO COMPOUNDS HAVING VALUABLE PHARMACOLOGICALPROPERTIES Filed May 16, 1963 3 Sheets-Sheet 2 INVENTORS IK OED WILLEMJ. ASMA ADOLF LINDN? United States Patent O sunsrrrrrrnn 'IERTAR AMINOCMPOUNDS HAVING VALUABLE PHARMACOLOGICAL rnornnrrns Tennis Kralt,Hendrik Dnrk Moed, and Willem Johannes This invention relates tosubstituted tertiary amino compounds having valuable pharrnacologicalproperties.

This application is a continuation-in-part of the applicants copendingapplication Serial Number 802,677, filed March 30, 1959 and nowabandoned and the applicants copending application Serial Number773,763, filed November 13, 1958 and now abandoned. Said applicationSerial Number 773,763 was a continuation-in-part of U.S. Serial No727,394, filed April 9, 1958 now abandoned.

In said parent applications the compounds recited were al1 described asbeing active in the lowering of blood pressure and as havingspasrnolytic activities. The compounds of the instant case are thosecompounds of the parent cases which are primarily useful as spasmolyticagents.

More particularly the compounds of the instant case arearalkylamino-esters of a nuclear substituted benzoic acid selected fromthe group consisting of the free base of the formula A wheren R and Rare each selected from the group consisting of hydrogen and alkoxy of1-4 carbon atoms, R is alkoxy of 1-4 carbon atoms, R; is selected fromthe group consisting of hydrogen and hydroxy, R is selected from thegroup consisting of hydrogen and alkyl of 1-4 carbon atoms, R is alkylof 1-6 carbon atoms, R, and R are each selected from the groupconsisting of hydrogen, hydroxy and alkoxy of 1-4 carbon atoms with theproviso that at least one of R and R is selected from the groupconsisting of hydroxy and alkoxy and Y is alkylene of 1-8 carbon atoms,the free base of the formule. B

wheren R R and R are each selected from the group consisting of H, OHand alkoxy of 1-4 carbon atoms, R; is selected from the group consistngof H and OH, R is alkyl of 1-4 carbon atoms, R is selected from thegroup consisting of alkyl of 1-6 carbon atoms and benzyl, Y is selectedfrom the group consisting of cyclohexene and alkylene of 1-8 carbonatoms, and R R and R are each selected from the group consisting of OHand alkoxy of 14 carbon atoms and their nontoxic acid addition salts.

Especially important in the compounds of -formula A is the combination:R is hydrogen and R is a hydroxy or an alkoxy group and the cases inWhich R and R are both either an alkoxy group or a hydroxy group.

If the left-hand and/or the right-hand benzene core contains more thanone alkoxy group, these compounds are preferred, in which thesesubstituents are identcal groups.

Patenized May 31, 1966 In the compounds according to the forrnula A, ifthe groups R R R and R represent alkoxy groups, they contan preferablyalower aliphatic carbon chain with 1 to 4 carbon atoms, particularly amthyl or an ethyl group.

In the compounds of the formula A to be described hereinafter the alkoxygroups of the left-hand and the right-hand benzene core are preferablybound to the para carbon atom, to the paraand to one meta-carbon atomand to the paraand the two meta-carbon atoms.

If in the compounds of the formula A R is an alkyl group, this containspreferably 1 to 4 carbon atoms and it is particularly a methyl group, Ris preferably an alkyl group having 1 to 6 carbon atoms, particularly analkyl group with 2 or 3 carbon atoms, for example an ethyl-, propylorisopropyl group. If Y designates an alkylene group, t contains 1 to 8carbon atoms, preferably 3 to 7 carbon atoms.

The compounds according to the invention may be producedin various ways.These methods are designated in the present application by AB, C, D andE.

In accordance with Method A a compound of the formula I (see formulasheet) reacts with one of the compounds of the formulae IIa, IIb andIIc. In these and in the further following formulae R to R and Ydesignate the groups or atoms as indicated above, unless it is statedotherwise. In formula Ilb R designates a lower aliphatic hydrocarbonradical, for example methyl or ethyl and Hlg indicates a chlorine or abromine atom. hydrogen, hydroxy or alkoxy of 1 to 4 carbon atoms.

According to Method B a compound of the ormula XII is coupled with acompound of the formula XIII. In the last-mentioned formula Medesignates a metal atom, preferably an alkali atom, for example, asodium atom or a potassium atorn. Hlg is a chlo'rine, bromine or iodineatom.

In accordance with Method C a compound of the formula XV reacts with acompound of the formula XVI. In the latter formula X designates achlorine, bromine or iodine atom or a ketoor aldehyde-oxygen atorn.

According to Method D into compounds of the formula XIX there isintroduced the group R where it clesignates a lower alkyl group, byreaction with a compound of the formula R Hlg, wheren Hlg designatesbromine or chlorine, or with dimethyl ordiethyl sulphate, if Rrepresents a methyl or ethyl group respectively.

In accordance with Method E compounds are produced, wheren R; is ahydroxy gronp, by hydrogenation of a compound of the formula XX.

The details of the Methods A to E are described hereinafter.

Method A.

This method is carried out in a manner known, in principle, for theesterification of an alcohol with an acid, an ester or an acid halide.The reaction takes place, preferably with an acid halide. The reactionmay be carried out with the reaction components as such, preferably insubstantially equimolar quantities, but it is advisable to carry out thereaction in the presence of a solvent. an acid halide, preferably thechloride, the solvent may be a liquid hydrocarbon, for example,petroleum ether, hexane, heptane, octane, an aromatic hydrocarbon, orexarnple benzene or toluene, furthermore tetrahydrofurane and variousother organic solvents, for example ethers such as diethyl ether,diisopropylether, furthermore acetone, chloroform or carbontetrachloride. reaction may take place at room temperature, but also byheating the reacton mixture, the maximum tempera- Further in theseformulae R designates If a compound of the formula I reacts with Theture being the boiling point of the reaction mixture. It is notnecessary to add an acid binder to the reaction mixture, since one ofthe starting substances, i.e. the compound of the formula I, isavailable as a free base and binds the hydrogen halide set free. Thereaction is performed fairly rapidly, i.e. after about 2 to 3 hours.

With the reaction of compounds of the formula I with an acid of theformula IIa Water is produced. For this reason it is interesting tocarry out the reaction so that the water produced is withdrawn directlyfrom the reaction mixture. It is therefore advisable to carry out thereaction in a solvent boiling at a fairly high temperature, for examplea solvent boiling at a temperature over 70 and distilling azeotropicallywith water. Such solvents may be benzene, toluene or xylene. As a rule,the duration of the reaction is longer than with the use of an acidhalide of the formula IIc.

In accordance with Method A the compounds according to the invention mayalsu be obtained by reacting a compound of the formula I with an esterof the formula IIb, preferably a methyl or ethy] e'ster. Although thisesterification method is suitable, in principle, it is less important inthe present case for practical purposes, since the alcohols of theformula I, which can be synthetized =only with some difficulty, must beavailable in an excess quantity to terminate completely a reaction withan ester of the formula IIb. If, nevertheless, this reaction is carriedout, it is advantageous to proceed so that the produced alcohol isremoVed, for example by distillation. In this case the excess quantityof the alcohol of the formula I may be chosen to be smaller.

In accordance with the aforesaid methods compounds may be produced inwhich R is a hydroxy-group; In this case it is important, however, thatin the starting substance of the formula I, R should designate either abenzylated hydroxy group or a keto group. After the termina-tion of theesterification either the benzyl group is separated out by the catalytichydrogenation or the keto group is converted into a hydroxy group byreduction, for example also by catalytic hydrogenation.

The compounds of the formula I which are sub stances not descrbedhit-herto, may be produced in various ways known per se for theproduction of substituted amino alcohols.

The starting material is, for example, a substituted aralkyl compound ofthe formula III, which is caused to react with an amino alcohol of theformula IV. The substituted aralkyl compound is, for example, an aralkylhalogenized in the aliphatic part, which aralkyl group may contain,moreover, a keto group in the alkyl portion. The amino alcohol is, forexample, ethanol amine, propanol amine.

In accordance with a second method of producing the amino alcohols ofthe general formula I the starting material is a substituted aralkylamine of the formula V. This compound of the formula V is reacted with,for example, a half-ester half-acid halide, pre f erably the acidchloride of the formula VI. In this formula Y is a divalent, branched ornonbranched alkylene radical with a chain of 0 to 7 carbon atorns, R isan aliphatic radical, for example, a methyl or an ethyl group. Thushalf-ester half-acid amide of the formula VII are produced. Thesehalf-ester half-acid amides may be reduced into the compound of theformula I with the aid of organic metal compounds, for example thosecontaining two different metal atoms, for instance lithiumaluminiumhydride or sodium-boron hydride.

In acco'rdance with a fur=ther method a compound of the formula V iscausd to react with a halide alcohol of the formula VIII. A variant ofthis method consists in that the starting material is not a halidealcohol, but a halide aldehyde or a halide ketone, this requiringafterwards a reduction into alcohol. According to a further method anamine of the formula V reacts with an epoxide, for example ethyleneoxide. This method is very suitable for the production of hydroxyamines.

A reaction of a different kind for the production of amino alcohols ofthe formula I consist in the catalytic reduction of a keto or analdehyde alcohol with amines of the formula V. If desired, the lattergroup of compounds may be a diketone or a dialdehyde, bui: this impliesthe risk that both the ca-rbonyl groups react each with an amino group.The catalytic reduction may, as is known, be carried out under theaction of a metal catalyst, for example, platinum, palladium or Raneynickel.

The method of catalytic hydrogenation may, as an alternative, be carriedout by starting from aralkyl ketones of the formula IX, which areconverted in the presence of amino alcohols of the formula X, bycatalytic hydrogenation, into amino alcohols of the formula I.

Method B The compounds according to the invention may also be producedby reacting a compound of the formula XII with a compound of the formulaXIII. In these formula XII contains, between the nitrogen atom andiodine atom and Me is a metal atom, for example a potassium atorn or asodium atom. If a compound of the formula XII contains, between thenitrogen atorn and the halogen atom, an alkylene chain of 4 or 5 carbonatoms, the re is a risk of ring closure, in which the halogen atomreacts with the nitrogen atom. Therefofe this method is less suitablefor the use of these starting materals.

With Method B the starting materal is preferably the free base. Thestarting material may also be a salt of the free amine, for example thehydrochloric acid salt, but in this case it is advisable to react onemoll of the salt of the compound of formula XII with 2 mols of thecompound of the formula XIII or, and this is a different possibili-ty,with one equivalent of the compound of formula XIII and an equivalent oflye, for example, diluted, aqueous sodium or potassium hydroxide.

As a solvent for the reaction of Method B use may be made of dlerentorganic solvents, for example, chloroform, acetonitrile, aromatichydrocarbons such as .benzene toluene or xylene; aliphatic hydrocarbonradicals are less suitable, since the reaction constituents are toolittle soluble herein. It is further advisable to carry out the reactionat the boiling temperature of the solvent. A normal reaction temperatrelies approximately between 70 and 130 C. The duration of the reaction isfairly long and, at the given temperature, it lies between approximately50 and hours.

The compounds of the formula XII may be produced by reacting thecorresponding alcohols with phosphorpentachloride, thionylchloride,phosphor tribromide or thionylbromide.

If the group R, is a hydroxyl group, it may be halogenized also in thesaid reaction. This may be avoided by benzylating the group R or byacylating it previously, for example by acetylating it.

This halogenation may, if desired, be c'arried out without using asolvent. Better results are often obtained when carrying out thereaction in the presence of a solvent.

Suitable solvents are: carbon tetrachlorde, benzene, toluene, in generalindifierent olvents. A further methcd of producing the compounds offormula XII consists in that compounds of formula V are reacted withcompounds of formula XIV. Preferably, at least one equimolar quantity ofa compound of formula XIV is used. The compound of the formula V ispreferably available in the form of the free base. The hydrogen halideproduced during the reaction is bound by the produced reactionsubstance.

In the description of Method B reference has been made to the risk ofcyclization. The risk thereof also exists in the present case, if acompound of the formula phosphoroxy chloride,

XIV contains, between the carbon atoms to which the halogen atoms arebound, two or three further carbon atorns.

Method C In order to obtan the compounds according to the invention thelast step of esterification with a nuclear substituted benzoylhalide,which may, if necessary, be followed by a further step, for example thecatalytic separation of benzyl groups or the reduction of any ketogroups, may be replaced by the production of substituted benzoyl estersof the formula XVI, which are reacted with compounds of the formula XV.In these formulae R to R and Y designate the groups and atoms referredto above, whereas X is a halide atom, for example a chlorine, bromine oran iodine atom or a double-boncled oxygen atom.

If X is a halogen atom, the reaction is preferably carried out so that 1mol of the compound of the formula XVI reacts with at least 1 mol of thefree base of the formula XV. Use is preferably made of 2 equivalents ofthe last-mentioned compound, 1 mol acting as an acid binder. As analternative, 1 equivalentof the compound XV and furthermore anequivalent of acid binder, for example a tertiary amine such aspyridine,collidine or triethanolamine may be used.

The reaction between a compound of the formulae XV and XVI (X=halogen)takes place preferably in, the presence of a solvent. To this end usemay be made of aromatic hydrocarbons, such as benzene, toluene, xylene,furthermore .chloroform, carbon tetrachloride, acetone, acetonitrile.

Also ethers, such as diethyl ether, diisopropyl ether, may be used.Moreover, in principle, aliphatic hydrocarbons may be used as a solvent.These compounds are, however, very little polar, so that the couplingreaction is performed usually very slowly.

It is advisable to carry out the reaction at a higher temperature. It issimplest to carry out the reaction at the boiling temperature of thesolvent. A temperature lying between 40 and 130 C. provides suitableresults.

The duraton of the reaction varies with hte choice of the solvent andthe reaction temperature. In this connection theduration of the reactionmay vary between. a few hours and about two days. If in the formula XVIX is a ketoor an aldehyde-oxygen atom, the reduction preferably takesplace with hydrogen and a metal catalyst. This catalytic hydrogenationmay be carried out with a noble metal, for example, platinum, palladiumor Raney nickel as catalysts. It is little advisable to use, as startingmaterial, compounds of the formula XV, in which R does not represent ahydrogen atom; if R is an alkyl group, high temperatures and pressuremust be used during the catalytic hydrogenation, for exampletemperatures between 100 and 200 and pressures between 10 and 100atmospheres. If desired, after ter-mination of the hydrogenation, byalkylation, the group R if it represents an alkyl-group, may beintroduced. The present method is less suitable for reactions betweenthose products in which the compounds of the formula XVI contain acarbon chain with less than 3 carbon atoms between the oxygen atom ofthe ester group and the oxygen atom X.

If such compounds were nevertheless used, this implies the complicationof hydrogenolysis of the ester.

If platinum or palladium is used as a catalyst, the hydrogenation may becarried out at,normal pressure and temperature, preferably in an acidmedium -or, if necessary, in a neutral or a weak alkaline medium. Thereaction is preferably carried out in the presence of dilutedhydrochloric acid, acetic acid or sulphuric acid. If desired, the freebase is subjected to a catalytic hydrogenation with a compound of theformula XVI.

The hydrogenation with Raney nickel is preferably carried out in analkaline medium and at a higher temperature and pressure. In order toobtain the alkaline medium it is not necessary to add lye. It suflicesto work with the freebase. As a rule, it is advs-able to choose the pHof the reaction medium between 8 and 11. If the free base is notsufficiently alkaline, the additon of diluted alkali, for example sodiumhydroxide or potassiurn hydroxide may increase the pH to the said value.

The temperature is preferably chosen to be between 60 C. and C., and thepressure between 1 and 10 atmospheres; the reaction may be carried outin the presence of a non-self-reducing solvent, which will preferably-be a lower aliphatic alcohol, for example ethanol, propanol,isopropanol or amyl alcohol, or mixtures thereof with water, thereaction mixture having -to be worked up so that ester interchangecannot occur. During the reduction ester interchange may sometirnesoccur. In this case use shuold be made of a further diluted alcohol as asolvent. As an alternative, the catalytic hydrogenation may be carriedout in water or in acetic acid or in mixtures thereof.

It should be noted that, if the staring substance of the formula XVcontained a benzyl'oxy group or a keto group, these functions areconverted during the coupling reaction into a hydroxy group.

Compounds of the formula XVI may be produced in different ways. Forexample a compound of the formula II is esterified with a halogenalcohol of the formula VIII. The esterifying reaction takes place onderconditions which are otherwise the same as referred to above foresterification reactions.

In order to produce compounds of the formula XVI, a compound of theformula II may be esterified with a dialcohol of the formula XVII. Thuscompounds of the formula XVIII are obtained. The esterification may takeplace again in the manner described above. It is advisable to carry outthe reaction with at least 1 equimolar quantity of the dialcohol inorder to avoid that compounds are obtained in which the two alcoholgroups are esterified. The hydroxy esters obtained may then be convertedby halogenation agents capable of replacing the hydroxy-group by ahalogen atom, into a compound of the formula XVI. The halogenationagents may be thionylchloride, phosphorpentachloride,phosphoroxychloride, phosphortribromide and thionylbromide.

In accordance with a third method compounds of the formula XVI may beproduced by esterifying a compound of the formula XIII, preferably analkali salt, for example the sodium salt, with an aliphatic dihalogencompound of the formula XIV. The reaction is again carried outpreferably with at least l equimolar quantity of the dihalogen compoundin order to avoid that also the second halogen atom participates in theesterification. The halogen compound is preferably the dichloro ordibromo compound.

Compounds of the formula XVI, in which X represents a double-bondedoxygen atom, may be produced by esterification of an acid or an acidhalide of the formula II with an aldehyde or a keto alcohol. Theesterification may, as an alternative, take place wtih a dialcohol,after which -the nonesterified alcohol group is oxidized into analdehyde or a keto group. In the latter case the esterification takesplace, preferably, with at least 1 equimolar quantity of the dialcohol.According to a third method the keto -or aldehyde esters are obtained byesterifying a compound of the formula XIII, preferably an alkali saltthereof, witha halogen ketone or a halogen aldehyde.

Method D In accordance with this method a compound of the formula XIXreacts with a halogen alkyl of the formula HlgR for example ClR If R isa methyl or an ethyl group, the desired compound may also be obtained byreacting a compound of the formula XIX with dimethyl or diethylsulphate. The reaction with a compound of the formula R Hlg ispreferably carried out with at least 1 mol of the free base of theformula XIX. Use is preferably made of 2 rnls of this compound to bindacid set free during the reaction. As an alternative, 1 mol of the freebase may be used and 1 mol of an acid binder may be added to thereaction medium, for example a tertiary amine, such as pyridine,collidine or triethanol amine or an inorganic carbonate such as sodiumorpotas sium-carbonate. As a solvent with this alkylatin reaction may beused aromatic hydrocarbons, for example benzene or toluene, furtherrnorechloroforrn, carbon tetrachloride, organic ethers, for example diethylor diisopropyl ethers, if desired even alcohols such as ethanol,propanol, isopropanol or butanol, provided the reaction conditions arechosen to be such that ester interchange cannot occur. If desired,tetrahydrofurane or dioxane may be used as solvents. The temperatures atwhich this reaction is preferably carried out vary between 40 and 120.The reaction may take place at room temperature, but preferably at theboiling point of the solvent. The duration of the reaction, which variesalso with the solvent used and the temperature of the reaction, is froma few hours to goed one day.

If use is made of a dialkylsulphate as an alkylation agent, use ispreferably made of an aqueous solution, whilst simultaneously with thedialkylsulphate lye is added, care being taken that the reaction mixturereacts invariably alkaline.

Method E It should finally be noted that the methods describedunder A toE serve as examples of the manner in which the compounds according tothe invention may be produced. The number of methods or combinationsthereof is not exhausted by this description. Neither methods described,nor the examples to be mentioned hereinafter are ntended to restrict theprotectve rights clamed.

EXAMPLES When reference is made in these examples to alcohol and ether,96% ethanol and di-ethyl ether respectively are meant, unless it isstated otherwise.

I. 2-(3,4'-dimethoxy-benzoylbxy) -[Nbutyl-2-(4"'- methoxyphenyl)ethylamno]-hexane (a) 5-butylamino-hexanol-Z.A solution of 43 g. (0.37mol) of 5-ketohexanol-Z (produced as described in Doklady Akad. Nauk.S.S.S.R. 88, 845 (1953)), 33 g. (0.45 mol) of butylamine in 150 m1. ofalcohol was hydrogenated at room temperature under atmospheric pres surewith platinum as a catalyst. When the absorption of hydrogen terminated,the reaction mixture was filtered ofi, the filtrate was acidified withconcentrated hydro chloric acid. The alcohol was evaporated and theresidue was -dissolved in water. This solution was washed with ether,then rendered alkaline and extracted three times with ether. The etheralextracts were dried on Na SO filtered, the ether evaporated and theresidue was distilled in vacuo. The yield was 20 g. (31%). Boiling point65 to 80 C./ 0.7 mm. Equivalent weight 178 (calculated 173).

(b) 5 [N-butyl 2'-(4"-methoxyphenyl)ethylamino] hexanol-2.A mixture of19 g. (0.11 mol). of 5-butylaminohexanol-2 and 8 g. (0.038 mol) of4-rnethoxyphenyl- 8 ethylbromide (produced as described in I. Org. Chem.9, 250 (1944)) was heated at to C. for 8 hours. After cooling 25 m1. ofdry ether was added and the mixture was left for 20 hours. Then 25 ml. 0water was added and the aqueous layer was separated off. The ether layerwas washed once with 10 ml. of water. The collected aqueous layers wereextracted twice with 10 ml. of ether. These thereal extracts were unitodwith the thereal layer and dried on Na SO The aqueous layer was found,by titration, to contain 0.037 equivalent Brions. The solution in etherwas filtered, the ether evaporated and the residue distilled in vacuo.The yield was 6.5 g. (57%). Boiling point 158 to 162 C. Eq. weight 310(calculated 307).

(c) 2 (3,4' dimethoxy benzoyloxy) 5 [N-butyl- 2"-(4"-methoxyphenyl)ethylamno] hexne.-To a solution of 3.1 g. (0.01 mol) of5-[N-butyl-2-(4"-methoxy phenyl)ethylamino] hexanol-2 in 80 ml. of drybenzene was added 2.1 g. (0.01 mol) of 3,4dimethoxybenzoylchloride andthis solution was boiled for 6 hours. After the evaporation of the'benzene, an -oil was obtained, which was dissolved in 15 m1. of 30%alcohol, rendered alkaline with 5 ml. of concentrated NH,OH and afterthe dilution withwater to 100 ml. it was extracted twice with 30 ml. ofether. The ethereal extracts were dried on Na SO filtered and the etherwas evaporated. The oil-like residue had a weight of 3.3 g. (=70%'). Eq.weight 472 (calculated 471). Ultraviolet absorption spectrum: max=262.5mu e, max 7850; max=285 ma 6 max=5,200.

II. 1-(3,4'-dimethoxy-benzoyloxy) 5-[N-methyl-Z- (4"'-amnophenyl)ethylamno] hexane-dihydrochlorde.

(a) 5-methylamno-hexanol-I.The production took place in accordance withthe method described sub Ia. Instead of using lplatinum, use was made ofRaney nickel as a catalyst. Since, after the first d-istillation, theequivalent weight was found to be too high, the substance was purifiedby dissolving the hydrochloride in water; this solution was washed withether and then rendered alkaline, after which it was extracted withether. The ethereal extracts were dried on Na SO filtered, the ether wasevaporated and the residue was again distilled in vacuo. The yield was30%. Boiling point 80 to 83 C./0.8/mm. Eq. weight (calculated 131).

(b) 5-[N-mezhyl-2-(4"ntrophenyl)ethylamino] hexanol-I.A solution of 7'g. of S-methylamino-hexanol-l (0.05 mol), 11.5 g. (0.05 mol) of2-(4-nitrophenyl) ethylbromide (produced as described in I. Am. Chem.Soc. 62, 1436 (1940)) and 7.5 g. (0.05 mol) of triethanolamine in 100m1. of absolute alcohol was boiled for 10 hours. Then the alcoholwasevaporated and to the residue was added 50 m1. of water and 200 ml.of ether. The ethereal layer was washed twice with 25 ml. of water. Theaqueous layer was found, by titration, to obtain 0.05 equivalent Brions. The ethereal layer was then extracted twice with 20 ml. of 0.15 Nhydrochloric acid. The aqueous solution thus obtained was renderedalkaline by 5 m1. of 50% sodium hydroxide solution and extracted twicewith 50 m1. of ether. The ethereal extracts were dried on Na SO filteredand the ether was Eq. weight 9 III. 1 (3',4' dmethoxy benzoyloxy) 4 [Nethyl- 1" methyl 2" (4"' methoxyphenyl)ethylamno] butane hydrochlorclehalf an hour, whilst stirring and cooling in a waterbath of roomtemperature, a solution of 24.7 g. (0.15 mol) of3-carbaethoxy-propionylchloride (see for its producton: I. Am. Chem.Soc. 60, 402 (1938)) in 150 ml. of dry benzene. The mixture was lboiled,whilst stirring, for 3 hours, cooled and the deposit formed was filteredof and washed with ether. The ether and the benzene were evaporated fromthe filtrate and the residue was distilled in vacuo. The yield was 46 g.(95%). Boiling point 172 to 175 C./0.1 mm.

(b) 4-[N-ezhfl-Imethyl-2-(4"-methoxyphenyl)ethylamino]butanol-Z.Asolution of 46 g. (0.15 mol) ofNN-ethyl-1-methyl-2'(4"methoxyphenynethyl 3-carbaethoxy-propionamide in200 ml. of dry ether was added, within 30 minutes, to a solution of 20g. (0.5 mol) of lithium-aluminum hydride in 500 ml. of dry ether. Themixture was then boiled for 20 hours. The reaction complex wasdecomposed with water and the deposit obtained was filtered off andwashed with ether. The solution in ether was dried on sodium sulphate,filtered, the ether evaporated and the residue was distilled in vacuo.The yield was 31 g. (78%). Boling point 158 to 163 C./0.08 mm. Eq.weight 257 (calculated 265).

(c) 1 (3,4 dmethoxy-benzoyloxy) 4 [N-ethyl-l" methylZ"-(4'-meth0xyphenyl)ethylamino]butane hydrochloride.-The production wascarried out by the method descrbed sub Ic by esterifying the compounddescrbed in the preceding paragraph with 3,4-dimethoxybenzoylchloride.The yield was 88%. Melting point 97 to 102 C. Chlorine content 7.68%(calculated 7.66% U.V. absorption spectrum: Mrnax=262.5 mu, e max=11,700; ;;max=285 ma, e rnax=6,000.

After crystallisation from methylethylketone the melting point wasraised to 105107 C.

Analyss.-Foundz C 74.71%, H 7.85%, N 2.97%.

Calc.: C 64,73%, H 7.83%, N 3.02%.

(a) 1-(3',4'-dimethoxyphenyl) 2-(N-ethylamno)propane.The production tookplace in accordance with the method des cribed sub Ia by hydrogenating amixture of 1-(3,4dimethoxyphenyl)propanone-Z (J. Am. Chem. Soc. 66, 26(1944)) and ethylamine with platnum as a catalyst. The yield was 81%.Boiling point 162 to 165 C./13 mrn. Eq. weight 229 (calculated 223).

(b) NN-ethyl-I' methyl 2-(3"4"dimethoxyphenyl)ehyl 3carbaethoxyproponamde. The production took place in accordance with themethod described sub IIIa by reacting the compound described in thepreceding paragraph with 3carbaethoxy-propionylchloride. The yield was100%. The nondistilled product was used for the following reaction:

(c) 4-[N-ethyl-1IJnethyl--(3"4"-dmethoxyphenyl) ethylamz'no]bucmolJ.-Theproduction took place in accordance with the method described sub IIIbby reducing the compound described in the preceding paragraph with asolution of lithium-aluminium hydride in ether. The yield was 70%.Boiling point 165 .to 168 C./0.08 mm. Eq. weight 297 (calculated 295).

(d) 1 (3,4 dmethoxy benzoyloxy)-4-[N-ethyl-I-methyl-2",3",4dmethoxyphenyl) ethylamino]butane. The production wascarried out in accordance with the method described sub Ic by esterifyngthe compound described in the preceding paragraph with3,4-dimethoxybenzoylchloride. T he hydrochloride would not crystallizefrom acetone, methyl-ethylketone, alcohol and mixtures of these solventswith ether. By dissolving the hydrochloride in water rendering thssolution alkaline with ammonia and extracting it with ether, the freebase was isolated. The yield was 93%. Eq. weight 460 (calculated 459).U.V. absorption spectrum: Mmax=262 II1,LL, e max=12000; Mrnax=287 mu, emax=7,320.

(a) J-(3'4'-dimethoxy-benzoyloxy)-6-brom-hexane. A suspension of 20.5 g.(0.1 mol) of a sodium salt of 3,4- dimethoxy-benzoic acid in a solutionof 30 g. (012 mol) of 1.6-dibrom-hexane in 250 m1. of dry acetonitrilwas boiled for hours. After cooling the deposit was filtered off. Theacetonitril was evaporated in vacuo frm the filtrate and the residue wasdistilled in vacuo. The yield was 14.5 g. (42%). Boiling point 202 to205 C./0.5 mm. Bromine content 25.8% (calculated 23.2 With thedistillation 16.5 g. of 1.6-dibrorn-hexane was reobtained.

(b) 1 (3,4' dz'methoxy-benz0yloxy)-6-[N-ethyl-I-methyl-2"-(4methoxyphenyl)ethylamno]hexane hydr0ch0ride.-A solution of15.5 g. (0.08 mol) of N-ethyllrnethyl2(4methoxyphenyl)ethylamine and13.8 g. (0.04 mol) of 1-(3,4'-dmethoxybenzoyloxy)-6-bromhexane in 100m1. of dry acetonitril was boiled for 100 hours. The acetonitril wasevaporated in vacuo and to the residue was added 75 ml. of dry ether.The deposit was filtered oi and the ether evaporated from the filtrate.The residue was dissolved in 20 m1. of 2 N-alcoholic hydrochloric acidand the alcohol was evaporated in vacuo. The residue was crystallizedfrom a mixture of 15 m1. of methyl-ethylketone, and 30 ml. of ether. Theyield was 15.5 g. (77%). Melting point 82 to 93 C. Chlorine content 7.8%(calculated 7.2%). U.V. absorption spectrum: Mmax=262 111/L, e max=12,400, Mmax=285 m e max=6,300.

After crystallisation from a mixture of methylethylketone and ether themelting point was raised to 95 to 98 C. Chlorine content 7.2%(calculated 7.2%).

Analysis.-Foundz C 65.84%, H 8.20%, N 3.06%. Calc.: C 65.70%, H 8.17%, N2.84%. This compound may be produced in a different manner.

(al) I-brom0-6-[N-ethyl-l"methyl-Z"-(4"-methoxyphenyl)ethylamno]hexanehydrobromde.-A solution of 19.3 g. (0.1 mol) ofN-ethyl-l-methyl2(4"methoxyphenyl)ethylamine and 24.4 g. (0.1 mol) of1,6-dibromhexane in 250 m1. of absolute alcohol was boiled for 4 hours.After cooling the reaction mixture was filtered off and the alcohol wasevaporated from the filtrate. To the residue was added 100 ml. ofacetone and after one day in the refrigerator the deposit was filtered 0and dried. The yield was 21 g. (48%). Bromine content (ionogeneous)19.7% (calculated 18.3%).

(bl) 1-(3',4dmethoxy-benzoyloxy) -6[N-ethyl-l"- methyl2"-(4'-methoxyphcnyl)ethylamin0]hexane hydrochlarde.-A suspension of 12g. (0.05 mol) of the Sodium salt of 3,4-dimethoxy-benzoic acid and 11 g.(0.025 mol) of the hydrobromide described in the preceding paragraph in250 m1. of dry acetonitril was boiled for 100 hours and the acetonitrilwas then evaporated in vacuo. To the residue was added 100 m1. of waterand 200 ml. of ether; the ethereal layer was isolated and the aqueouslayer extractecl once with 50 m1. of ether. The ethereal extracts werecollected, washed twice with 50 ml. of water, dried on sodium sulphateand filtered. To the filtrate was added 25 m1. of 2 N-alcoholhydrochloric acid and the deposit was filtered off. The deposit wascrystallized from a mixture of 10 ml. of niethylethylketone and 20 m1.of ether. The yield was 6.7 g. (50%). Melting point 93 to 96 C. Chlorinecontent 7.4% (calculated 7.2%

(a) N,N ethyl 2 (4 ethoxyphenyl)ethyl 3-carbaethoxy-propz'onamde.-Theproduction was carried out by the method described sub IIIa by reactingN-ethyl-2- (4-ethoxyphenyl)ethylamine with3-carbaethoxy-propionylchloride. However, in this case not the amineitself, but triethylamine wasused as an acid binder. The crude reactionproduct (48 g.=100%) was used directly for the following reaction.

(b) 4 [N ethyl-2-(4"-ethoxyphenyl)ethylamino]- butanol-J .The productionwas carried out by the method described sub IIIb by reducng the compounddescribed in the Preceding paragraph with lithium-aluminium hydride. Theyield was 36%. Boiling point 155 to 157 C./0.1 mm. Eq. weight 270(calculated 265).

(c) 1 (4 methoxy-benzoyloxy)-4-[Nethyl2"-(4"'- ethoxyphenyl)ethylamno]butane hydrochloride.-The production took place by carrying out themethod descrbed sub Ic by esterifying the compound described in thepreceding paragraph with 4-methoxy-benzoylchloride. The yield was 74%.Melting point 103 to 104 C. Chlorine content 8.20%. (calculated 8.14%).U.V. absorption spectrum: =258 m t e 17,800.

Anaylsis.Found: C 66.05%, H 7.99%, N 3.19%. Calc.: C 66.19%, H 7.87%,N3.22%.

V11. 1 (4 methoxy-benzoyloxy-4-[N-ethyl-l"-methyl- 2"-(4-ethoxyphenylethylamno] butanehydrochlaride 2-(4" ethoxyphenyl)ethylamino] butanehydrochlrde.-The production took place by carryin-g out the methoddescribed sub Ic by esterifying the compound described in the precedingparagraph with 4-methoxybenzoylchloride. The yield. was 80%. Meltingpoint 83 to 86 C. Chlorine content 7.93% (calculated 7.89%). U.V.absorption spectrum: =258 mu, e =l7,40.

Analysis.-Fondz C 64.67%, H 8.11%, N 3.07%. Calc.: C 66.80%, H 8.07%, N3.11%.

VIII. 1 (4ethoxybenzoyloxy-4-[N-ethyl-l-methyl-2" (4"'-ethoxyphenyl)ethylamno] .butane hydrochloride The production took place by carryingout the methoddescribed under Ic by esterifying the c-ompound describedVIIc of 4-[N-ethyl-1-methyl-2-(4-ethoxyphenyl)ethylamino butanol-l with4-ethoxybenzoylchloride. The yield was 87%. Melting point 113 to 114 C.Chlorine content 7.50% (calculated 7.65%). U.V. absorption spectrum:=257. m e 17,300.

Analyss.-Found: C 67.63%, H 8.47%, N 3.08%. Calc.: C 67.37%, H 8.27%, N3.03%.

IX. I-(4'-hydroxy-benzoyloxy)-4-[N-ethyl 1" methyl- 2" (4ethoxyphenyl)ethylamino] butane hydrochloride (a)1-(4-benzyloxy-benzoyloxy)-4-[N-ethyll"-methyl- 2" (4ethoxyphenyl)ethylamno] butane-hydrochlride.The production took place bycarrying out the method described sub Ic by esterifying the compounddescribed in the paragraph VIIc of 4-[N-ethyl-l'-methyl-Z'-(4-ethoxyphenyl)ethylamino] butanol-1 with 4-benzyl- 12oxy-benzoylchloride. The yield was 86%. Melting point 114 to 117 C.Chlorine content 6.73% (calculated 6.78%

(b) 1 (4-hydroxy-benz0yloxy)-4-[N-ethyl-I-methyl- Z"-(4"'-ethoxyphenyl)ethylamino] butane-hydrochlorde. 5.23 g. (0.01 mol) of the compounddescribed in the preceding paragraph was dissolved in 75 m1. of alcohol.Thereto was added a prehydrogenated, acid-tree palladium catalyst,obtained from 150 mg. of palladium chloride and 750 mg. of decolouringcarbon and hydrogenated. After the calculated quantity of hydrogen andbeen absorbed, the catalyst was filtered ofi and the filtrate wasthckened to dryness in vacuo. The residue was crystallzed from 25 ml. ofacetone, filtered 0 and dried. The yield was 3.55 g. (82%). Meltng point129 to 130 C. Chlorine content 8.14% (calculated 8.18%). U.V. absorptionspectrum: =259 m;r, e =17,100.

Analysis.-Found: C 66.41% H 8.07%, N 3.20%. Calc.: C 66.49%, H 7.91%, N3.24%.

X. I-(4'-methoxy-benzyloxy) 4 [N-ethyl 1" methyl- 2"-(3'",4'5"'trimethoxyphenyl)ethlamino] butanehydrochlorde (a)N,N-ethyl-l-methyl-Z-(3,4",5"-trimethoxylphenly)ethyl-3-carbaethoxyproponamde.The production took place by carrying out the method described sub IIIaby racting N ethyl 1' methyl-2'-(3"4",5-trirnethoxyphenyl)ethylaminewith 3-carbaethoxypropionylchloride. However, not the amine itself, buttriethylamine was used as an acid binder. The conversion took placequantitatively. The crude product was used for the following reaction.

(b) 4 [N-ethyl 1-methyl-Z-(3",4,5"-rimeth0xy phenyl)ethylamino]butanol-1.The production was carried out by the method described sub llbby reducing the compound described in the preceding paragraph withlithium-aluminiumhydride. The yield was 45%. Boiling point 182 to 186C./0.05 mrn. Eq. weight 318 (calculated 325).

(c) 1 (4-methoxy-benzoyloxy)-4-[N-ethyl-l"-metlzyl- 2" (3',4'5trimethoxyphenyl)ethylamno]butane. The production was carried out by themethod described sub Ic by esterifying the compound described in thepreceding paragraph with 4-methoxy-benzoylchloride. The yield was 61%.U.V. absorption spectrum: =254 to 258 nm, s 17,300. Eq. weight 470(calculated 459).

XI. 1-(3',4',5-trimethoxy-benzoyloxy)-4-(N ethyl 2"- phenylethylamz'no)-butane.

(a)N,N-ethyl-2'-phenylethyl 3carbaethoxy propionicamde.-To a soluton of33.7 g. (0.226 mol) of Nethyl 2-phenylethylamine in m1. of dry ether wasadded, within 15 minutes, while stirring and cooling in a water bath ofroom temperature, a solution of 18.4 g. (0.112 mol) of3-carbaethoxy-propionyl chloride (for the production thereof see: I. Am.Chem. Soc. 60, 402 (1938)) in 50 m1. of dry ether. The mixture wasboiled, while stirring, for two hours, cooled and the precipitationproduced was iltered 0 and washed with ether. The ethereal solution wasdried on sodium sulphate, after having been washed twice with 40 ml. ofwater. After the filteration the ether was evaporated and the residuewas dstilled in vacuo. The yield was 25 g. (64%). Boilng point 172 to175 C./0.1 mm.

(b) 4 (N ethyl-Z'phenylethylamno)butanol-I.A solution of 25 g. (0.09mol) of N,N-ethyl-2-phenylethyl- 3-carbaethoxy-propionic amide in 100m1. of dry ether was added, within 25 minutes, while stirring, to asolution of 15 g. 0.4 mol) of lithium-aluminium hydride in 350 m1. ofdry ether. The mixture was boiled, while stirring, for 16 hours. Thereaction mixture was decomposed with water and the precipitationproduced was filtered of]? and washed with ether. The ethereal soluti'onwas dried on sodium sulphate. and filtered ol. After the evaporation 13of the ether, the residue was distilled in vacuo. The yield was 15 g.(80%). Boiling point 132 C./0.5 mm. Eq. weght 221 (calculated 221).

(c) 1 (3',4,5' trz'methoxy benzoyloxy) 4 (N- ethyl-2"-phenyl-ethylamino)butane.-To a solution of 4.4 g. (0.02 mol)4-(N-ethyl-2-phenylethylamino) butanol-l in 50 ml. of dry benzene wasadded, while cooling with water of room temperature, within 20 minutes asolution of 6.9 g. (0.03 mol) 34,5-trimethoxy-benzoylchloride (I. Am.Chem. Soc. 73, 144 (1951)) in 40 m1. of dry benzene. After the additionthe reaction mixture was boiled for three hours. After evaporation ofthe benzene the residue was dissolved in acetone. Thus a small quantityof precipitation was obtairred, which was filtered o. The acetone wasevaporated from the filtrate and the residue was dssolved in 60 ml. ofwater. The aqueous solution was alkalized with 1 N ammonia and extractedthree times with 50 m1. of ether. The ethereal solution was dried onsodium sulphate and filtered oi. After the evaporation of the ether, anoil was obtained. T he yield was quantitative. Equivalent weight 417(calculatecl 415). Methoxyl content 22.43% (calculated 22.41%).Ultraviolet absorption spectrum: ,,.=265 m e,=10380. Spasm. act. 4 to 5.

Production the bimxalate.-The free base of 1-(3',4',5'-trimethoxy-benzoyloxy) 4-(N-ethyl-2"phenylethylamino)butane andoxalic acid were dissolved in equimolar quantities in acetone. After theaddition of ether a crystallinic substance was precpitated. Meltingpoint 120 to 123 C. (sintering at 118 C.). 0.5 g. was crystallized from3 mm. of alcohol. Melting point 123 to 125 C. After anothercrystallization from alcohol the melting point was 127 to 129 C.

AnaIysis.-Foundt C 62.04%, I-I 6.96%, N 2.98%,

3.07%, 2.82%, 2.93%, 0CH 18.16%. Calc.: C 61.78% H 6.93%, N 2.77%, OCH18.42%.

Producton of the hydrochlorde.2.4 g. of the free base was dissolved inabsolute alcohol and an equimolar quantity of 0.27 N alcoholichydrochloric acid was added. T he alcohol was evaporated and the residuedissolved in acetone. To this solution was added ether until turbiditywas produced. After a stay in a refrigerator (5 C.) crystallizationoccurred. The precipitate was filtered ofi". The weight was 2.8 g.Chlorine content 7.87% (calculated 7.86%). Melting point 103 to 104 C.After crystallization from a mixture of 5 m1. of methylethylketone andm1. of ether, 2.2 g. of the substance was obtained; melting point 106 to108 C. U.V. spectrum: =265 to 267.5 m;r, e 10,400.

Analyss.-Found: C 63.61%, H 7.52%, N 3.00%. Calc.: C 63.79%, H 7.53%, N3.11%.

(a) N,N benzyl 2 phenylethyl 3 czzrbaethoxyproponc amde.To a solution of21.1 g. (0.1 mol) of N-benzyl-2-phenylethylamine and 7.9 g. (0.1 mol) ofdry pyridine in 75 ml. of dry ether was added, within 20 minutes, whilestirring, a solution of 16.5 g. (0.1 mol) of3carbaethoxy-propionylchloride in 25 ml. of dry ether. During theaddition a further 125 ml. of dry ether was added to the reactionmixture, since stirring was rendered diflicult by the precipitateproduced. After the addition the reactionmixture was boiled, whilestirring, for one and a half hours. After cooling the precipitate formedwas filtered off and washed with ether. The ethereal solution was washedwith 40 ml. of water, dried on Na SO and filtered. The ether wasevaporated from the filtrate and the residue was distilled in vacuo. Theyield was 27 g. (80% Boiling point 217 to 219 C./0.03

(b) 4 (N benzyl 2 phenylezfhylamno)butanol- I.A solution of 37 g. (0.11mol) of N,N-benzyl2- phenylethyl-3-carbaethoxypropionic amide in 200 ml.of

14 dry ether was added, within 15 minutes, to a solution of 8.5 g. (0.22mol) of lithium-aluminium hydride in 300 m1. of dry ether. After theaddition the mixture was boiled for 20 hours, while stirring. Thereaction mixture was decomposed with water and the precipitate producedwas filtered off and washed with ether. The ethereal solution was clriedon sodium sulphate and filtered oi. After the evaporation of the etherthe residue was distilled in vacuo. The yield was 19.5 g. (65%). Boilingpoint 185 to 189 C./0.8 mm. Eq. weight 282 (calculated 283).

(c) 1.- (3',4',5 trz'methoxy benzoyloxy) 4 (N-benzyl-2"-plzenylethylamno) butane hydrochloride. To a solution of 8.5g. (0.03 mol) of 4-(Nbenzyl-2- phenylethylamino)butanol-1 in 40 m1. ofbenzene was added, while stirring at room temperature, within 15minutes, 6.9 g. (0.03 mol) of 34,5-trimethoxybenzoylchloride. Thereaction mixture was boiled for two and a half hours, while stirring,after which the benzene was evaporated in vacuo. The residue wascrystallized from a mixture of 15 ml. of acetone and 15 ml. of ether.The yield was 14 g. (91%). Chlorine content 6.82% (calculated 6.91%After crystallization from acetone, the melting point was 134 to 136 C.U.V. absorption spectrum: l =265 m -e=9,900.

Anayss.-Found: C 67.36%, H 7.02%, N 2.76%, OCH3 18.19%. Calc.: C 67.77%,H 7.01%, N 2.72%, OCH 18.11%. Spasm. act. 3.

X111. 1(3,4,5-trimethoxy-benzoyloxy)-4-(N-ethyl-J"-methyl-2phenylethylamino) buttme hydrochlorde (a) N,N ethyl 1 methyl 2phenylethyl 3- carbaezhoxy-propionc amz'de.To a solution of 14.2 g.(0.09 mol) of Nethyl-lnethyl-2-phenylamine and 6.9 g. (0.09 mol) ofpyridine in 50 ml. of dry benzene was added, within 20 minutes, whilestirring, at room temperature, 14.4 g. (0.09 mol) of2-carbaethoxy-propionylchloride. After the addition the mixture wasboiled while stirring, for two hours. After cooling the reaction mixturehad added to it m1. of dry ether. The reaction mixture was filtered off,a precipitate being separated out, which, subsequent to drying, provedto have a weight of 10 g. and a chlorine content of 29.1%. The solventwas evaporated from the filtrate, after which the residue was distilledin vacuo. The yield was 19.5 g. (77%). Boiling point 170 to 174 C./0.08mm.

(b) 4 (N ethyl 1 methyl -2' phenylezhylamno) bumnol-I.A solution of 19g. (0.065 mol) of N,N- ethyl 1 methyl 2 phenylethyl 3carbaethoxypropionic amide in ml. of dry ether was added, within 30minutes, while stirring, to a solution of 8 g. (0.21 mol) oflithium-aluminium hydride in 300 m1. of dry ether. After the additionthe mixture was boiled, while stirring, for 20 hours. The reactioncomplex was, while cooled in an ice bath, decomposed with water and theprecipitate formed was filtered off and washed with ether. The etherealsolution was dried on sodium sulphate and filtered off. After the etherhad been evaporated, the residue was distilled in vacuo. The yield was11.6 g. (75%). Boiling point 118 to 122 C./0.1 mm.. Eq. weight 231(calculated 23 5).

(c) 1 (3',4',5' trimethoxy-benzoyloxy) 4 (N-ethyl-J"-methyl-2"-plzenylethylamino)butane hydrochlorde.-To a solutionof 7.05 g. (0.03 mol) of 4(N-ethyl-1'-methyl-2'-phenylethylamino)butanol-l in 50 ml. of dry benzene wasadded, within 10 minutes, while stirring, a solution of 6.91 g. (0.03mol) of 3,45-trimethoxy-benzoylchloride in 50 In]. of dry benzene. Thenthe reaction mixture was boiled for three hours, while stirring and thebenzene evaporated in vacuo. The residue was dissolved in a mixture of15 m1. of methyl-ethylketone and 15 ml. of ether. The crystals producedwere filtered ofr. The yield was 8.4 g. (60%). The substance proved tobe very hygroscopic and even after one night of drying in vacuo onphosphorus pentoxicle t proved to contain 15 moisture. Melting point 68to 74 C. Eq. weight 480 (calculated 465.5). U. V. absorption spectrum:

Spasm. act. 15.

The substance was converted into the free base and the ol was analysed.Eq. weight 428 (calculated 429).

Analysis.Foundz C 69.35, 69.45%; H 8.10, 7.87%; N 3.30, 3.26%; OCH21.72%. Calc.: C 69.93%, H 8.16%, N 3.26%, OCH 21.68%.

XIV. I (3',4,5' zrimethoxy benzoyloxy) 6 (N- ethyl-2-phenylethylaminohexane (a) 1 (3',4',5' trmethoxy benzoyloxy) 6 bromohexane.-Thiscompound was produced in two ways, which are described in this exampleunder (1) and (2).

( 1) A suspension of 23.5 g. (0.1 mol) of the sodium salt of3,4,5-trimethoxy-benzoic acid in a solution of 24.5 g. (0.1 mol) of1,6-dibromohexane in 50 m1. of xylene was kept for 60 hours in a bath of150 C. After Cooling the preciptate was filtered ofi; the xylene wasevaporated from the filtrate in vacuo and the residue was dstilled invacuo. The yield was 10.5 g. (29%). Boiling point 187 to 189 C./0.1 mm.Bromine content 22.22% (calculated 21.33). By distillation 14.4 g. of1,6-dbromohexane was regained.

(2) 1 (3,4'5' trmethoxy benzoyloxy) 6 bromohexane.-23.S g. (0.1 mol) ofthe sodium salt of 3,4,5-trimethoxybenzoic acid and 30 g. (0.12 mol) of1,6-dibromohexane was added to 300 ml. of anhydrous acetonitrile and themixture was boiled for 43 hours. The precipitate was filtered ofi andwashed with ether. The filtrate was inspissated in vacuo and to theresidue was added 150 m1. of ether. The precipitate was filtered off andthe ether was vaporated from the filtrate. The residue was distilled invacuo. The yield was 16.5 g. (44%). Boiling point 186 to 191 C./0.08 mm.Bromine content 24.2% (calculated 21.3%

(b) 1 (3,4',5 trimethoxy benzoyloxy) 6 (N-ethyl-2"-phenylethylamro)hexane.A solution of 10.3

bromohexane and 9 g. (0.06 mol) of N-ethyl-2-phenylethylarnne in 75 ml.of dry benzenewas boiled for 70 hours. The benzene was subsequentlyevaporated in vacuo and to the residue was added 100 ml. of dry ether.The precipitate formed was filtered ofl and the ether was evaporatedfrom the filtrate. The oily residue had a weight of 11.9 g. and anequivalent weight of 376 (calculated 443). By adding 1 N alcoholchydrochloric acid solution the substance was converted into thehydrochloride. A few eorts to crystallize this hydrochloride trommethylethylketone, ether and alcohol ether failed. The hydrochloride wasobtained in the form of an oil, by evaporating the solvents, anddissolved in 150 ml. of water. This solution was extracted twce with 40m1. of ether and then alkalized with 10 ml. of concentrated ammonia,after whch extraction was carried out three times with 50 m1. of ether.The ethereal solution was dried on sodium sulphate, filtered off and theether was evaporated from the filtrate. The residue was found to containN-ethyl-2-phenylethylarnine and was therefore kept :at 120 C./1 rnm. forthree hours. The yield was 2.4 .g. (18%). Eq. weght 440 (calculated443). U. V. absorption spectrum: =265 mu, e,=11000.

Analysis.-Foundz C 70.02, 69.94%; H 8.43, 8.26%; N 3.07, 3.04%. Calc.: C70.04%, H 8.35%, N 3.16%.

350 mg. of the base was converted with alcoholic hydrochloric acid intothe hydrochloride, which was crystallized from a mixture ofmethylethylketone and ether.

XV. 1 (3',4',5' trinethoxy benzoyloxy) 4 (N propyl 1" methyl 2" hydroxy2" phenylethylamrzo)butane hydrochlorde (a) 4 (N propyl 1 methyl2-oxo-2'-phenylethylamno)butanol-l.-A solution of 6.4 g. (0.03 mol) of1- oxo-l-phenyl-2-bromopropane and 7.9 g. (0.06 mol) of4-propylamino-butanol-l in 35 ml. of absolute alcohol was boiled for 15hours. The alcohol was then evaporated and to the residue was added 50ml. of ether and 35 m1. of water. The layers were separated and theether layer was extracted three times with 10 ml. 2 N hydrochloric acid.The three extracts were united and alkalized with 10 ml. of 50% caustcsoda and then extracted three times with ether. The ethereal solutionwas dried on sodium sulphate, filtered o and the ether evaporated fromthe filtrate. The residue was 7 g. (89%). Eq. weight 259 (calculated263).

(b) 1 (3',4',5'-trmethoxy benzoyloxy) 4 (N- pr0pyl 1" methyl -2" 0x0 2"phenylethylamirzo) butane hydrochloride.-To a solution of 6.85 g. (0.026mol) of 4 (N propyl-lmethyl-2-oxo-2-phenylethylamino)butanol-l in 50 m1.of dry benzene was added, within 15 minutes, while stirring, at roomtemperature a solution of 6.35 g. (0.027 mol) of 3,4,5-trmethoxy-bemzoylchloride in 50 ml. of dry benzene. After the addition the reactionmixture was boiled for three hours and the benzene was evaporated invacuo. The residue was dissolved in a mixture of 25 m1. ofmethyl-ethylketone and 25 m1. of ether. The preciptate was filtered oand yielded 3 g. of hygroscopic substance having a chlorine content of6.79% (calculated 7.19%). Evaporation of the filtrate to 10 m1. yieldeda further quantity of hygroscopic substance of 4.5 g. having a chlorinecontent of 7.19% (calculated 7.19% Yield 7.5 g. (58%). Doublecrystallisation trom methylethylketone yielded crystals having a meltingpoint of 76 to 79 C.

Analyss.-Fonndt C 62.88%, H 7.39%, N 2.86%, Cl 7.09%, OCH;, 19.15%.Calc.: C 63.22%, H 7.29%, N 2.84%, Cl 7.19%, OCH 18.84%.

(c) 1 (3,4,5' trmethoxy benzoyloxy) 4 (N- propyl 1" methyl 2" hydroxy 2"phenylethylamino)butane hydrochlorde.-To a solution of 2.1 g. (0.0043mol) of the compound obtained in accordance with Example XVIIb in 50 ml.of 80% alcohol was added palladium catalyst (obtained by hydrogenationof a suspension of 80 mg. of palladium chloride and 350 mg. ofdecolouring carbon); the mixture was hydrogenated. The hydrogenabsorption was performed slowly, so that the hydrogenation was twiceinterrupted to add fresh catalyst. 116 ml. of hydrogen was absorbed. Thereaction mixture was filtered and the solvent was evaporated from thefiltrate. The residue was dissolved in a mixture of acetone and etherand kept in the refrigerator. The precipitate was filtered o and dried.The yield was 0.65 g. (31%). Meltng point 133 to 135 C.

After crystallisation from a mixture of alcohol and ether, the meltingpoint was 144 to 145 C. U.V. absorptien spectrum =265 1I1u, e =ll60. Theacetoneether filtrate of the first crystallisation was evaporated andthe residue dissolved in an alcohol-ether mixture. This yielded a secondquantity of crystals: 018 g. (8.5% Melting point 136 to 138 C. U.V.adsorption spectrum =265 m e =11,000. Spasm. act. 30.

Analysis.-Foundz C 62.89, 62.53%; H 7.60, 7.58%; N 2.82, 2.79%. Calc: C62.96%, H 7.67%, N 2.82%.

(a) I-(4'-benzyloxyphenyl)-2-ntropropene-I.A solution of 100 g. (0.472mol) of 4-benzylxy4venzaldehyde (J. Chem. 800. 1935, 1540), 47 g. (0.627mol) of nitroethane and 24 ml. of butylamne in 275 ml. of dry toluenewas boiled for 6 hours and the water formed was separated out bydistillation. After 6 hours of boiling,

about 9 g. of water had been produced. The toluene was evaporated invacuo and to the residue was added 150 m1. of petroleum ether (4060 C.).The precipitate was filtered otf, washed with petroleum ether (40- 60)and dried. The yield was 65 g. (51%). Meltng point 132 to 143 C.Crystallsation from tetrahydrofurane yielded yellow, transparent scales,having a melting point of 147 to 148 C.

(b) 1methyl- 2 (4'-benzyloxy)phenylethylamine.-A solution of 45 g.(0.167 mol) of l(4"-benzyloxyphenyl)- 2-nitropropene-l in 500 m1. of drytetrahydrofurane was added, within 45 minutes, to a solution of 30 g.(0.8 mol) of lithium-aluminium hydride in 300 ml of drytetrahydrofurane. After the addtion the mixture was hoiled, whilestirring, for two hours and the reaction mixture was decomposedsubsequently with water, while cooled on ice. The precipitate wasfiltered off and washed with ether. The solvent was evaporated from thefiltrate and the res due was distilled in vacuo. The yield was 26 g.(68%). Boiling point 148 to 152 C./0.07 mm. Melting point 103 to 104 C.Eq. weight 243 (calculated 241).

(c) N acetyl 1 methyl-Z(4'benzyloxy)phenylethylamz'ne.24 g. (0.1 mol) ofl-methyl-2-(4'benzyloxy) phenylethylarnine was boiled with 100 ml. ofacetic acid anhydride for half an hour. The acetic acid anhydride wasevaporated in vacuo and to the residue was added 50 ml. of ether. Theprecipitate was filtered o1f and washed with 25 ml. of ether. The yieldwas 23.5 g. (84%). Melting point 123 to 124 C.

((1) N ethyl methyl-2(4'-benzyloxy)phenylethylamne.-The substance wasproduced in the manner described in Example 1b; the diference =being,however, that tetrahydrofurane instead of ether and N-acetyl-l-methyl-2-(4-benzyloxy)phenylethylamine was used as starting substance. Theyield was 75%. Boiling point 139 to 142 C./0.2 mm. Eq. weight 269(calculated 269).

(e) N,N ethyl 1 methyl2-(4"-benzyloay)phenylethyl-3-carbaethoxypropionicamz'de.The sulbstance was produced in the manner described in ExampleXIIa. The yield was 47%.

(f) 4 [Nethyl-1'-methyl2-(4"-benzyl0xy)plzenylet/zylamino]-butanol-I.Thissubstance was produced in the manner described in Example XIb byreducing the compound obtained in the manner described in the precedingparagraph with lithium-aluminium hydride The yield was 50%. Boilingpoint 186 to 191 C./0.08 rnm. Eq. weight 344 (calculated 341).

(g) 1 (3'4,5' trmethoxy-benzoyloxy)-4-[Nethyl- 1 methyl 2(4-benzyloxyphenyl)ethylamne] bumne hydrochlorz'de.-This substance wasproduced in the manner described in Example XIc by reacting the compoundobtained by the method described in the preceding paragraph with3,4,5-trmethoxybenzoylchloride. The yield was 95%. The hydrochlorde didnot crystallize. The crude product was therefore hydrogenated.

(h) 1 (34',5 zrmethoxy-benzoyloxy-4-[N-etlzyl- 1 methyl 2(4"'hydroxyphenyl)ethylamno] butane.'lhe method of producing was similarto that described in Exa-mple XVc by hydrogenating the compound obtainedby the method described in the preceding paragraph with palladiumcatalyst and hydrogen, the dierence being, however, that in thiscase 96%alcohol was employed instead of 80% alcohol. The substance was separatedout as a free base. The yield was 25 g. (40%). Eq. weight 430(calculated 445 Producton of the lzydrchlorde.-O.S g. of the free basewas dissolved in the calculated quantity of 0.27 N- alcoholichydrochloric acid. The alcohol was evaporated and the residue wasdissolved in a mixture of acetone and ether. The precipitate wasfiltered off and dried. The filtrate had a weight of 0.22 g. Meltingpoint 135 to 136 C. U.V. -a=bsorpton spectrum =267.5 to 270 mu, e=600.Spasm. act. 50.

18 Analyss.*Foundz C 62.39, 62.47'%; H 7.61, 7.64%; N 2.91%; Cl 7.37%.Calc.: 62.36%, H 7.48%; N 2.91%, C17.37%

XVII. 1-(3',4,5-trmethoxy-benzoyloxy)4[N-ehyl-I"- methyl 2"(4-methoxyphenyl)et/zylamino]bmane hydrochlorde (a) N,N ethyl 1'methyl-2(4"-methoxyphenyl) ethyl 3 carbaethoxypropionc amide.-The methodof producing was similar to that described in Example XIIa by reacting Nethyl 2 (4'-methoxyphenyl)ethylamine with 3-carbaethoxypropionicchloride. The yield was 75%. Boling point 176 to 181 C./0.08 mm.

(b) 4 [N ethyl 1 methyl-2(4-methoxyphenyl) chylamino]bmanol-L-The methodof producing was similar to that described in Example Xl b by reducngthe compound obtained in XVIIa with lithium-aluminium hydride. The yieldwas 82%. Boiling point 172 to 179 C./0.2 mm. Eq. weight 265 (calculated265).

(c) 1 (34',5' trimethoxy benzoyloxy)-4-[N-ethyl- 1" methyl 2" (4'' gmethoxyphenyl)ethylamirro] Imzane-hydrochlorde.-The method of producingwas similar to that described in Exarnple XIc by coupling the compoundobtained in XVIb with 3,45-trimethoxybenzoylchloride. The yield was 69%.The hydrochloride crystalized from methylethylketone with 1 mol of thissolvent. This complex had a rnelting point of 77 to 81 C. After thecrystallisation from alcohol-ether the hydrochloride was obtained.Melting point 129 to 130 C. U.V. Absorption spectrum =270 m e,=11,200.

Analysis.Found: C 63.11%, H 7.69%, N 2.77, 2.72%; OCH 25.11%. Calc.:62.96% H 7.67%, N 2.82%, OCH 25.06%. Spasm. act. 125.

XVIII. l-(4',5'trimethoxy-benzoyloxy) 4-[N-ezhyl-I"- methyl 2" hydroxy-2(4" hydroxyphenyl)ethylamino] butane hydrochlorde (a) 4-[N ethyl 1methyl-2oxo-Z-(4-benzyloxyphenyl)ethylamino] butanol-I.The method ofproducing was similar to that described in Example XVa by reacting 1-(4'benzyloxyphenyl)-l-oxo-2-brorno-propane with 4-ethyl-amino-butanol-l.The yield was 38%. Eq. weight 354 (calculated 355).

(b) 1-(3,4,5'-trimetlzoxy-benzoyl0xy) 4-[N-ethyl-I-methyl-Z"-oxo-2"-(4"'-benzyloxyphenyl)ethylamino] butane.-The method ofproducing was similar to that described in Example XIc by reacting thecompound obtained in XVIIIa with 3,4,5-trimethoxybenzoylchloride. Theyield was 80%. Melting point 148 to 152 C. Chlorine content 6.43%(calculated 6.06%). Crystallzation from a mixture of alcohol and etheryielded a substance having a melting point of 152 to 153 C. U.V.absorption spectrum =272.5 m;r, e,=31000.

Analysis-Found: C 65.40%, H 6.89%, N 2.32%, OCH 15.79%. Calc.: C 65.58%,H 7.17%, N 2.39%, OCH 15.88%.

(c) 1(3',4,5 trimethoxy-benzoyloxy)-4-[N-ethyll methyl 2-hydroxy-Z-(4-hydroxyphenyl)ethylamino] butane hydrochlorde.The method ofproducing was similar to that described in Exarnple XVcthe differencebeing, however, that in this case 96% alcohol nstead of 80% alcohol wasused and that, moreover, the compound obtained in XVIIIb was employed asa starting material. The yield was 10%. Melting point 178 to 180 C. U.V.absorption spectrum =267.5 to 270 Illu, e 12,400.

Analyss.-Foundz C 59.42%, H 7.30%, N 2.80%. Calc.: C 60.30%, H 7.24%, N2.82%. Spasm. act. 75 to 100.

X1X. 1-(3,4'5'-trimethoxy-benzoyloxy) 4-[N-propyl-I- metlzyl 2"hydroxy-Z"-(4"benzyloxyphenyl)ethylamno] buane hydrochloride (a)4-[N-propyl 1 methyl-2'-0x0 2'-(4"-benzyloxyphenyl)ethylamno]butanol-J.The method of produc- N 2.74%, OCH 18.18%.

'XX. 1-(3',4,5-trmethoxy-benzoyloxy) 4-[1 "-methyl-Z"- Analyszs.-Found:C 65.37%, H 7.02%, N 2.30%,

Cl 6.10%, OCH 15.84%. Calc.: C 66.05%, H 7.34%, N 2.33%, Cl 5.92%, OCH15.51%.

(c) 1-(3'4,5-trimethoxy-benzoyloxy) 4 [N-propyl- 1" methyl 2" 0x0 2 (4'hydroxyphenyl)ethylamino] bmane hydrochloride.The method of producingwas similar to that described in Example XVIIIc by hydrogenating thecompound obtained by the method descrbed in the preceding paragraph withpalladium and hydrogen. After 1 mol of hydrogen had been absorbed, thereaction was terminated. The yield was 92%. Melting point 192 to 193 C.U.V. absorptior'1 spectrum 7\ =275 m e =20,600; =285 mu,e =2,00.

Analysis.-Found C 61.21%; H 7.10%; N 2.68, 2.61%; Cl 6.97%. Calc.: C61.23%, H 7.07%, N 2.75%, C1 6.97%.

(d) 1-(3'4'5 trimethoxy-benzoyloxy) 4-[N-propylamino] bmanehydrochloride.-The method of producng was similar to that descrbed inExample XVc by hydrogenating the compound obtained by the methoddescribed in the preceding paragraph with palladium and hydrogen, thediflerence being, however, that in ths case use was made of 75% alcohol,instead of 80% alcohol.

The yield was 60%. Melting point 165 to 168 C. U.V. absorpton spectrum:=267.5 to 270 In .=10,200.

AnalyssFoundz C 60.38%; H 7.43%; N 2.79%, 2.72%; OCH 17.82%. Calc.: C60.99%, H 7.43%,

Spasm. act. 50.

hydroxy 2 (4-hydroxyphenyl) ezhylamino] butane lzydrochloridephenyl)ethylamino] butanol-l.-The method of producing was similar tothat described in Example XVa by reacting 1(4-benzyloxyphenyl)-loxo-2-bromopropane with 4-benzylamino-butanol-l.The yield was 88%. Eq. weght 460 (calculated 417). This crude productwas used further.

(b) 1(3,4',5'- zrimethoxy-benzoyloxy) 4-[N-benzyl- 1-methyl-Z"-0xo-2-(4"benzyloxyphenyl)ethylamno] butane hydrochlorde.-The method of producingwas similar to that described in Example Xlc by reacting the compoundobtaned by the method described in the preceding paragraph with3,4,5-trimethoxy-benzoylchloride. The yield was 100%. Chlorine content5.04% (calculated 5.48%). This crude product was used for furtherpurposes.

(c) 1-(3',45' trimethoxy-benzoyloxy)-4-[l-methyl-2"-0x02-(4"-hydroxyphenyl)ethylamino] butane hydrochlorde.-Thissubstance was produced by the method described in Exarnple XVc byreacting the compound obtained by the method described in the precedingparagraph with palladium catalyst and hydrogen. After the absorption of2 mols of hydrogen the hydrogenaton was terminated. Use was made of 85%alcohol as a solvent for the compound to be hydrogenated. The yield was55%. Melting point 135 to 137 C. U.V. absorption spectrum: =275 rnu, e=21,800; 7\ =285 my., e =21,8()0.

Example XXIa with lithium-aluminium hydride.

Analyss.Found: C 58.97%, H 6.55%, C1 7.63%. Calc.: C 59.04%, H 6.42%, Cl7.59%.

(d) 1-(3',4,5 trmethoxy-benzoyloxy)-4-[l"-methyl-2"-hydroxy-Z-(4'-lzydroxyphenyl)ethylamno] butane hydrochlorde.Theproduction was the same as that described in Example XVc byhydrogenating with palladium and hydrogen of the compound obtained inXXc. Use was made of 75% alcohol as a solvent for the compound to behydrogenated. The. yield was 82%. Melting point 190 to 191 C. U.V.absorption spectrum: =267.5 mu. to 270 mu., e =11,000.

Analyss.Found: C 58.31, 58.65%; H 6.70, 6.88%; N 2.96, 2.97%. Calc.: C58.79%, H 6.82%, N 2.98%. Spasm. act. 0.5.

XXI. 1-(3',4',5'-trimeth0xy-benzoyloxy)-4- (N-propyl-2"-phenylethylamno) butane hydrochlora'e (a) N.N-propyl-2-phenylethyl-3-carbaethoxy-propionic amde.-A solution of 13g. (0.08 mol) of 3-carbaethoxy propinoyl-chloride in 70 ml. of drybenzene was added slowly in drops to a solution of 28 g. (0.16 mol) ofN- propyl-2-phenylethylamine in m1. of dry benzene. After the addtionthe mixture was boiled for two hours and kept at room temperature forone n-ight. The reaction mixture was filtered of and the benzeneevaporated from the filtrate. The residue was dsso lved in 100 ml. ofdry ether and aftertwo days the precipitate was filtered off again. Thefiltrate was inspssated and the residue distilled in vacuo. The yieldwas 22 g. (88%). Boiling point to C./0.04 mm.

(b) 4-(N propyl 2 phenylethylamino)butanol-l The product-ion was carriedout by the method described in Example Xlb by reducing the compoundobtained in The yield was 75%. Boiling point 140 to 142 C./0.7 rum. Eq.weight 235 (calculated 234).

(c) 1-(3,4,5' trimethoxy benzolyoxy)-4-(N-propyl- 2 phenylezhylamno)butane hydrochloride.--This substance was produced by the methoddescribed in Example XIc by reacting the compound obtained in XXIb with34,5-trimethoXy-benzoylchlorde. The hydrochlorida was crystallized froma mixture of methylethylketone and ether in a ratio of 3:5. The yieldwas 47%. Melting point 87 to 89 C. Chlorine content 7.61% (calculated7.62%). Spasm. act. 20. U.V. absorption spectrum: =266 In,u, ,=10100.

Analysis.-Foundz C 64.22, 64.73%; H 7.65, 7.80%; N 3.04, 3.11%. Calc.: C64.45%, H 7.95%, N 3.01%.

XXH. 1 (3,4',5 trimethoxy-benzoyloxy) 4-[N-propyl-1-methyl-2-(4'hydroxyphenyl)ethylamno] butane hydrochloride (a) Npropionyl 1 methyl-2 (4-benzyloayphenyl) ethylamine.This substance wasproduced by the method described in Example XVIc by boilingl-methyl-2-(4- benzyloxyphenyl)ethylamine with propionc acid anhydride.The yield was 78%. Melti ng point 95 to 96 C.

(b) N propyl l-methyl-2(4benzyloxyphenyl)ethylamne.This substance wasproduced by the method described in Example XVId by reducing thecompound obtained by the method described in the preceding paragraphwith lithium-aluminium hydride. The yield was 77%. Boiling point 172 toC./0.6 mm. Eq. weght 289 (calculated 284).

(c) N,N propyl 1 methyl-2'-(4"-benzyloxyphenyl) ethyl 3carbaethoxy-proponc amde.The production was carried out by the methoddescribed in Example XXIa by reacting the compound obtained by themethod described in the preceding paragraph with 3-carbaethoxypropionylchloride. The yield was 87%. Boiling point 208 to 214 C./0.5mm.

(d) 4 [N-pr0pyl- 1methyl-2-(4'Fbenzyloxyphenyl) etlzylamno]butanol-I.The production was carried out by the method described inExample Xlb by reducing the compound obtained by the method described inthe pre- 21 ceding paragraph with lithium-aluminium hydride. The yieldwas 60%. Boiling point 200 to 205 C./0.1 mm. Eq. weight 358 (calculated355).

(e) 1 (3,4',5' trimethoxy-benzoyloxy) 4-[N-propyl- 1"methyl-2-(4"-benzyloxyphenyl)ezhylamino]butane hydrochloride.-Theproduction was sirnlar to the method described in Example XIc while thecompound obtained by the method descrbed in the preceding paragraph wasreacted with 34,5-trimethoxy-benzoylchloride. The yield was 60%. Meltingpoint 138 to 141 C. Chlorne content 6.1% (calculated 6.6%).

(f) 1 (3',4,5' trimethoxy-benzoyloxy) 4-[N-propyl- 1"methyl2-(4"-hydroxyphenyl)ethylamino]butane hydrochloride.-The substancewas produced by the method described in Example XVc by hydrogenating thecompound obtained by the method descrbed in the preceding paragraph. Theyield was 72%. Melting point 172 to 173 C. Chlorine content 7.36%(calculated 7.17%). U.V. absorption spectrum: =268 m,u, e =10,900.Spasm. act. 50.

Analyss.Foundz C 63.11, 63.17%; H 7.76, 7.75%; N 2.55, 2.50%. Calc.: C62,97%, H 7.67%, N 2.83%.

XXII. 1-(3'4',5' rmethoxy benzoyloxy 4-(N-propyl- 1"-methyl-2"-phenylethylamino) buzane hydrochlorde (a) N,N propyl 1'methyl-2'-phenylethyl-carbaethoxyprapionc amde.The substance wasproduced by the method described in Exarnpe XXIa by reacting 3-carbaethoxy-propionyl chloride with N-propyll-methyl-2-phenylethylarnine. The yield was 68%. 154 to 158 C./0.02 rnm.

(b) 4 (N -propyl-l-methyl-2-phenylethylamno)butanol.This substance wasproduced by the method described in Exarnple XIb by reducing thecompound obtained by the method described in the precedng paragraph withlithium-aluminium hydride. The yield was 80%. Boiling point 144 to 146C./0.65 min. Eq. weight 246 (calculated 249).

(c) 1 (3,45' trmethoxy-benzoyloxy) 4-(N-propyl- 1" methyl 2pherzylethylamino)butane hydrochlorde.-The prodnction was carried outsimilar to the meth- 0d described in Example XIc by reactng the compoundobtaned by the method described in the preceding paragraph with34,5-trimethoxy-benzoylchlorde. The yield was 86%. Melting point 125 to126 C. Clorne content 7.2% (calculated 7.39%). U.V. absorption spectrum:=266 rnu, e =10,300. Spasrn. act. 20.

Analyss.-Foundz C 64.36, 64.45%; H 7.96, 7.84%; N 3.11, 2.92%. Calc.: C65.07% H 793%, N 2.92%.

XXIV. 1-(3',4',5-trimetlzoxy-benzoyloxy) 6-[I-methyl-2"-(4"'-methoxyphenyl)ethylamino]hexane hydrochlorde A solution of 7.7g. (0.04 mol) of Nethyl-l-methyl-2- (4'-methoxyphenyl)ethylamine and 6.6g. (0.02 mol) of 1 (3,4,5-trimethoxybenzoyloxy)-6-bromohexane in 501111. of dry acetontrile was boiled for 90 hours. The acetonitrile wasevaporated in vacno and to the residue was added 50 m1. of dry ether.The precipitate was fi1- tered off and the ether evaporated from thefiltrate. The residue was dissolved in 45 1111. of 0.5 N hydrochloricacid and this soluton was washed twce with 25 m1. of ether. The waterlayer was alkalized with m1. of concentrated ammonia and extracted threetimes with 30 m1. of ether. The ethereal extracts were dried on Na SOfiltered and the ether evaporated. The residue was kept, for threehours, in vacuo (0.1 mm.) at 90 C. and then dissoved in 24 m1. of 0.76 Nalcoholic hydrochloric acid. The alcohol was evaporated and the residuecrystallized from a mixture of m1. of methyl-ethyl ketone and 10 m1. ofether. The yield was 6.0 g. (60%). Meltng point 137 to 140 C. Chlorinecontent 7.03% (calculated 6.78%). U.V. absorption spectrum: =267.5 me,=12,600.

Boling point XXV. 1 (3',4,5 trimethoxy-benz0yloxy) 3 [N-ethyl-1"-methyl-2(4-methoxyphenyl) ethylamno] propane (a) 1 (3,4',5trmethoxy-benzoyloxy)-3bromopropane.The prodncton was carried outsimilar to the method described in XIV a by esterifyng the sodium saltof 3,4,5-trimethoxy-benzoic acid with 1.3 dibromopropane. The yield was52%. Boiling point 165 to 169 C./0.3 mm. Bromine content 23.7%(calculated 24%).

(b) Z-(3',4',5' trimezhoxy benzoyloxy) 3-[N-ethyl- 1" methyl-Z (4"'methoxyphenyl) ethylamino] propane.-The production was smlar to themethod described in XXIV by couplng the compound described in theprecedng paragraph with N-ethyIJ-rnethyl-2-(4-methoxyphenyl)ethylarnine. The yield was 54%. Eq. weight 432 (calculated445). U.V. absorption spectrum: =27.5 m e =11,600. Spasm. act. 25.

XXVI. 1-(3,4,5-trethoxy-benzoyloxy) 4-(N-propyl-I"-methyl-2"-phenylethylamno)butane hydrochlorde The production was Carriedout by a method similar to the method described under Xc by esterifying4-(N- propyl l'-methyl-2-phenyl ethylamino)butanol-l (sec XXIIb) with34,5-trirnethoxybenzoylchloride. The yield wa Meltng point 123 to 124 C.Chlorine content 6.77% (calculated 6.81%). U.V. absorption spectrum:=266 m e =9,600.

Analysis.-Foundz C 67.15%, H 8.36%, N 2.74%. Calc.: C 66.73%, H 8.44%, N2.68%.

XXVII. 1-(3,4',5'trimethoxy-benzoyloxy) 4-[N-ethyl-1-methyl-2"-(4-methoxyphenyl)ethylamno] bmane hydrochlorize Theproducton was smilar to the method described in XIc by esterifying4-[N-ethyl-1'-rnethyl-2-(4methoxyphenyl)ethylamino]butanol-1 (see XVIb)with 3,45 trimethoxy benzoylchloride. The yield was 75%. Melting point92 to 106 C. Chlorne content 6.93% (calculated 6.60% U.V. absorptionspectrum: =27 nm, e =l0.200. Crystallization from methyiethyl ketoneyielded a substance having a meltng point of 119 to 120 C. Spasm. act.'30.

XXVIII. 1 (3',4,5 trmethoxy-benzoyloxy) 4 [N- ethyl 1 methyl 2 (3,4dimethovcyphenyl) ethylamno]butane hydrochloride (a)I-(3',4'-dimethoxyphenyl) 2(N-ethylamno)propane.-The method use'd was acatalytic hydrogenation of a mixture of1-(3',4'-dirnethoxyphenyl)propanone-2 (I. Am. Chern. Soc. 66, 26 (1944))and ethylamine with platinum as a catalyst. The yield was 81%. Boilingpoint 162 to 165 C./ 13 mm. Eq. weght 229 (calculated 223).

(b) N,N ethyl 1 methyl 2(3",4"-dimethoxyphenyl)ethyl-3-carbaetlzoxy-propionic amde.-Thissubstance was produced by a method smilar to the method described inXXIa by reacting the compound described in the preceding paragraph with3-carbaethoxy-propionyl chloride. The yield was 100%. The nondstilledproduct was employed for the reaction to be described hereinafter.

(c) 4 [N-ethyl-Z'metlzyl2-3,4"-dimethvxyphenyl)] ezhylamno butanol-J.Themethod used was similar to the method described in Xb by reducing thecompound descrbed in the preceding paragraph with a solution oflithium-aluminium hydride in ether. The yield was 70%. Boiling point 165to 168 C./0.08 mm. Eq. weight 297 (calculated 295).

(d) 1-(3,4,5'-trimethoxy-benzoyloxy) 4-[N-ezhyl-I- mezhyl 2"(3',4"-dmeflzoxyphenyl)ethylamna]butarze hydrochloride.The productioriwas carried out by a method similar to the method described in XIc byesterifying the compound described in the preceding paragraph with34,5-trimethoxy-benzoylchloride. The yield was 70%. Melting point 129 to132 C. Chlorne content 6.78% (calculated 6.76%). U.V. absorptionspectrum: =269 m/u, e 12,600. Crystallsation from meth- XXXV.

25 Analysis.-Fund: 0 57.72% I-I 7.57%, N 2.81%, ocnr 16.73%. C811C2 c61.00%, H 7.43%, N 2.74%, ocra 18.18%.

(2.) 1-(3',4,5-rmethoxybenzoyloxy) -b10m0penuwer-The production wascarried out similar to the method described in XIVa by esterfying thesodiurn salt of 3,45-rrimethoxy-benzoic acid with 1,5-dibromopentane.The yield was 56%. Boiling point 182 to 196 C./0.05 mm. Melting point7981 C. Bromine content 22.2% (calculated 22.1%

(b) 1-(3,4,5'-trimethoxy-benmyloxy)5-[N-ethyl-I"- methyl2"-(4"methoxyphenyl)ethylamin0]pentane. The production was sirnilar tothe method described in XXIV by coupling the compound described in theprecedng paragraph with N-ethyl-l-methyl 2(4-methoxyphenyl)ethylamine.The yield was 58%. Eq. weight 473 (calculated 473). U.V. absorptionspectrum: =267 m;r, e =11,900. Spasm. act. 250.

Analyszs.-Foundz C 67.76% H 8.40%, N 2.71%. Calc: C 67.56%, H 8.21%, N2.96%.

Ths product was preparcd according to the same method as set out inExample XXI. First 3-carbaethoxy propionylchloride was reacted withN-ethyl 2-(2-me- Ths product was prepared according to the same processas indicated in the foregoing examples. Firstly l-[N-ethyl-2-(3"-methoxyphenyl)-l-methyl ethylamino] 3- carbaethoky propionicamide (boiling point 184190 C./ 0.3 mm. Hg) was prepared from3-carbaethoxy propionyl chloride and N-ethyl2-(3"methoxyphenyl)-l'-methyl ethylarnine. Then the carbaethoxy compoundwas reduced to obtain 4-[N-ethyl-2'-(3-methoxyphenyl)l'- rnethylethylamino] butanol-l (boiling point 148 152 0/ 0.4 mm. Hg) whichcompound was esterified with 3,4,5-trirnethoxy benzoic acid to obtainthe compound as mentioned in the beginning of this example afteracidifying with HC1. Melting point of the substance 119.5 122 C. U.V.absorption spectrum: =269 m, =11,900

Analyszs.-C 63.07%; (calc. 62.97% H 7.75% (calc. 7.67%), N 2.86% (calc.2.83%), C1 7.16% (calc. 7.16% Spasm. act.: Doryl-papaverine 65-125; BaCl=papaverine 5-10.

XXXIX. 1-(3'4,5-trimethoxy-benzoyloxy)-5-[N-ethyl 2"-(2 mehoxyphenyl) 1melhyl ethylamno] pentane.

The procedure was the same as indicated in Example XXXVI. =28 m;r, e=11.500.

Analyss: C 68.35% (calc. 68.56%), H 8.25% (calc. 8.31%), N 3.11% (calc.2.96%). Hydrochloride salt rnelting point 1111 14 C.; Cl content 7.20%(calc. 6.95%). U.V. absorptin spectrum: =267 m e =11.900. Spasm. act.:Doryl-papaverinc=65 BaCl;,-papaverine=S-IO.

The antispasmodic activity of the neurotropic type of the compounds ofthe invention was determined in vitro against carbarninoylchlorene(Doryl) by the method of Magnus, described in Pfliigers Archiv (102,page 123 and ff. (1904)). By this method there is measured thecontraction of an intestine under the action of a solution of knownconcentration of carbarninoylcholine, i.e. a spasmogen having aneurotropic eect. It is then determined which concentration ofpapaverine is required to obviate the said contraction for 50% and thenthe concentration of a compound to be tested which is also capable toobviate the said contraction for 50%. The quotient of the concentrationof papaverine and the tested compound producing the obviation of 50%, isa measure for the antispasmodic activity (in .his case of neurotropicnature). Ths activity is also indicated in the tables.

If previously a fairly high antispasrnodic eiect of neurotropic naturein vitro had been ascertained with compounds of the invention, anantispasmodic effect of musculotropic nature is measured by use ofbarium chloride as a spasrnogen.

For the increasing of spasmolytic activity it has been found that alkoxygroups present on the left hand benzene nucleus of the compounds ofFormula A should preferably be methoxy or ethoxy, particularly at thepara or para and meta positions,R should be preferably alkyl,particularly methyl.

A particular group of compounds of Formula A having a high spasmolyticactivity are those compounds in which R is hydrogen, R is hydrogen oralkoxy of 1 to 4 carbon atorns, R is hydrogen or hydroxy, R is hydrogenor alkyl of 1 to 4 carbon atoms, R is alkyl of 1 to 6 carbon atoms, Y isalkylene of 3 to 7 carbon atoms, R is hydrogen or alkoxy and R isalkoxy.

A particularly preferred group of these latter compounds are those inwhich R is hydrogen, R is hydrogen, para-methoxy or para-ethoxy, R ismeta-methoxy, or meta-ethoxy, R; is hydrogen, R is hydrogen or methyl, Ris alkyl of 2 to 3 carbon atoms, Y is alkylene of 4 to 6 carbon atoms, Ris hydrogen, para-methoxy or paraethoxy and R is meta-methoxy ormeta-ethoxy.

In the compounds of our invention falling within the scope of Formula Bit has been found that the following groupings of substituents tend toincrease the spasmolytic activity:

I. The group in which:

R and R are hydrogen, R is hydrogen or para-hydroxy, R, is hydrogen orhydroxy, R is methyl, R is alkyl of 1 to 5 carbon atorns, Y is alkyleneof 1 to 8 carbon atoms or an alkyl-cyclohexyl group and R R and R areeach methoxy bound to carbon atoms 3, 4 and 5 of the righthand benzenenucleus;

II. The group in which:

R is hydrogen or meta-methoxy, R is para-methoxy, R; is hydrogen, R; ishydrogen, R is methyl, R is alkyl of 1 to 4 carbon atoms, Y is alkyleneof 2 to 8 carbon atoms and R7, R and R are methoxy or ethoxy atpositions 3, 4 and 5 respectively of the right-hand benzene nucleus.

Finally a group of compounds falling within the scope of Formula Bhaving spasmo.lytic activity of both neurotropic and musculotropicnature are those compounds in which R and R are hydrogen, R ispara-ethoxy or paramethoxy, R; is hydrogen or hydroxy, R is methyl, R isalkyl of 2 to 3 carbon atorns, Y is alkylene of 2 to 5 carbon atoms andR R and R are methoxy groups joined to the right-hand benzene nucleus atthe 3, 4 and 5 positions.

29 ach selected from the group consstng of OH and alkoxy of 1-4 carbonatoms and ther non-toxic acid additon salts.

2. A compound of the formula CH CH3 l OOH; C Ha 3. A compound of theformula 11. A compound of the formula oc H;

0 no@c Ho HNC mc momomo- OCHs (!H3 (JJH2 l z References Cited by theExaminer 10 FOREIGN PATENTS UNITED STATES PATENTS 232,206 2/ 1926 GreatBritan.

2,404691 7/ 1946 Christansen et al. 260-473 2,650230 8/1953 CusicLORRAINE A. WEINBERGER, Prlmary Exammer. 2,995492 8/1961 Biel 260+294.315

3,004976 10/1961 Marxer 260-294.3

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3254112May 31, 1966 Teunis Kralt et al It is hereby certfed that error appearsin the above numbered patent requiring correction and that the sadLetters Patent should read as corrected below.

Column 4, line 22, strike out "formula Xll contains, between thenitrogen atom and" and nsert 1nstead formulae Hlg is a chlorine atom, abromne atom or an column 8, lnes 8 and 9, for "thereal", eachoccurrence, read ethereal line 29, for "2, read a column 9,

line 43, for "7471%" read 6471% line 71, for "methyl 2 3 4 read methyl-2 [3 4 column 10, line 70, for "alcohol" read alcoholic column ll, line28, for "l-(4-methoxy" read l- [4methoxy column 12, line 11, for "and"read had line 35, for "IIb" read IIIb column 15, line 27', for "21.33"read 2l.33% column l, line 62, for "adsorpton" read absorption columnl7, line 6, for "152" read 142 column l8, line 2, for "62.56" read C62,36% line 32, for "62.96%" read C 62,96% column 2l, line 34, for"tanol," read tanol-l line 50, for "795%" read 793% column 22, l1ne 36,for "trimethoxy" read criethoxy line 60, for "2-3," read 2 [3" column 25line 23 for "8 21%" read 8.31% column 26, line 9, for"carbaminoylchlorene" read carbaminoylcholine columns 27 and 28, 1n thetable for Compounds of Formula B", column 4, l1ne 2 thereof, for H readH same table, column l line 19 thereof, for "oOCH read mOCIL same table,column line 19 thereof, for "nC H reed C ,H columns 29 and 30, for theporton of the formule in claim 5 reading read

1. AN ARALKYLAMINO ESTER OF A NUCLEAR SUBSTITUTED BENZOIC ACID SELECTEDFROM THE GROUP CONSISTING OF THE FREE BASE OF THE FORMULA: